ECTS Abstracts (2015) 1 OC6.6

Blood circulating miRNAs are indicative of skeletal fractures in postmenopausal women with and without type 2 diabetes and may be promising candidates for general fracture risk prediction

Ursula Heilmeier1, Matthias Hackl3, Susanna Skalicky3, Fabian Schroeder4, Klemens Vierlinger4, Andrew J Burghardt1, Ann V Schwartz5, Johannes Grillari2 & Thomas M Link1

1Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA; 2Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria; 3TAmiRNA GmbH, Vienna, Austria; 4Austrian Institute of Technology, Vienna, Austria; 5Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Fracture risk in type-2-diabetes (T2D) and postmenopausal osteoporosis is routinely assessed with FRAX or DXA although these methods show limitations especially in T2Diabetics. Novel, general applicable biomarkers are therefore desirable. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis (“osteomiRs”) and T2D aetiology. The objective of this study was to analyse circulating miRNAs in a well-characterised study of postmenopausal and diabetic osteoporosis and to evaluate their utility for general fracture risk assessment. MiRNA-qPCR-arrays and differential-expression-analysis of 153 miRNAs were performed from 74 serum samples drawn from postmenopausal T2D women with (DMFX, n=19) and without fracture history (DM, n=19) as well as from non-diabetic women with (Fx, n=19) and without fracture history (Co, n=17). Group-wise non-parametric statistical comparisons were used with BH-adjustment of p-values for multiple testing. Circulating miRNAs exhibiting significant differences were then used for building multi-parametric models to differentiate fracture patients from controls. Cumulative ROC analyses yielded AUC-values of 0.978 for Fx/Co-comparisons (based on 4 miRNAs) and 0.933 for DMFX/DM-comparisons (based on 4 miRNAs). Interestingly, the 4 highly discriminative miRNAs of each comparison did not overlap. We found that some of them have been previously described as “osteomiRs”, such as miR-155-5p, an initiator of osteoclastogenic differentiation, or miR 96-5p, an osteocyte negative marker. All remaining ones had not been previously characterised (e.g. miR-188-3p and miR-203a) yet. Therefore, additional in vitro tests were performed, to characterise their (anti)-osteogenic activity. Our data provide first evidence that certain circulating miRNA levels are indicative of fragility fractures in postmenopausal women with and without diabetes and may be novel candidates for general fracture risk screenings. Future studies will elucidate if this knowledge can be used to improve current diagnostic techniques to predict fracture risk and therapy response in elderly women.

Disclosure: Susanna Skalicky: employee at TamiRNA; Matthias Hackl: COO at TamiRNA.

Johannes Grillari: scientific advisor TamiRNA, CEO of evercyte.GmbH. The study was funded by EU_FP7 Frailomic (JG, SKA), NIH RC1 AR058405 (TML), NIH R01 AR060700 (AJB), AWS Preseedgrant (MH).